title: Evidence for a role of sterol 27-hydroxylase in glucocorticoid metabolism in vivo.
abstract: The intracellular availability of glucocorticoids is regulated by the enzymes 11β-hydroxysteroid dehydrogenase 1 (HSD11B1) and 11β-hydroxysteroid dehydrogenase 2 (HSD11B2). The activity of HSD11B1 is measured in the urine based on the (tetrahydrocortisol+5α-tetrahydrocortisol)/tetrahydrocortisone ((THF+5α-THF)/THE) ratio in humans and the (tetrahydrocorticosterone+5α-tetrahydrocorticosterone)/tetrahydrodehydrocorticosterone ((THB+5α-THB)/THA) ratio in mice. The cortisol/cortisone (F/E) ratio in humans and the corticosterone/11-dehydrocorticosterone (B/A) ratio in mice are markers of the activity of HSD11B2. In vitro agonist treatment of liver X receptor (LXR) down-regulates the activity of HSD11B1. Sterol 27-hydroxylase (CYP27A1) catalyses the first step in the alternative pathway of bile acid synthesis by hydroxylating cholesterol to 27-hydroxycholesterol (27-OHC). Since 27-OHC is a natural ligand for LXR, we hypothesised that CYP27A1 deficiency may up-regulate the activity of HSD11B1. In a patient with cerebrotendinous xanthomatosis carrying a loss-of-function mutation in CYP27A1, the plasma concentrations of 27-OHC were dramatically reduced (3.8 vs 90-140 ng/ml in healthy controls) and the urinary ratios of (THF+5α-THF)/THE and F/E were increased, demonstrating enhanced HSD11B1 and diminished HSD11B2 activities. Similarly, in Cyp27a1 knockout (KO) mice, the plasma concentrations of 27-OHC were undetectable (<1 vs 25-120 ng/ml in Cyp27a1 WT mice). The urinary ratio of (THB+5α-THB)/THA was fourfold and that of B/A was twofold higher in KO mice than in their WT littermates. The (THB+5α-THB)/THA ratio was also significantly increased in the plasma, liver and kidney of KO mice. In the liver of these mice, the increase in the concentrations of active glucocorticoids was due to increased liver weight as a consequence of Cyp27a1 deficiency. In vitro, 27-OHC acts as an inhibitor of the activity of HSD11B1. Our studies suggest that the expression of CYP27A1 modulates the concentrations of active glucocorticoids in both humans and mice and in vitro.
authors.affiliation: Department of Nephrology, Hypertension and Clinical Pharmacology, University Hospital Berne, CH-3010 Berne, Switzerland Department of Neurology, University Hospital Zurich, Zurich, Switzerland Department of Medicine, University of California, San Francisco, California, USA Department of Internal Medicine, Emmental Hospital, Burgdorf, Switzerland Prince Henry's Institute, Clayton 3168, Victoria, Australia.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vögeli
authors.forename: Hans H
authors.initials: HH
authors.lastname: Jung
authors.forename: Bernhard
authors.initials: B
authors.lastname: Dick
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Erickson
authors.forename: Robert
authors.initials: R
authors.lastname: Escher
authors.forename: John W
authors.initials: JW
authors.lastname: Funder
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Frey
authors.forename: Geneviève
authors.initials: G
authors.lastname: Escher
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism; D000818:Animals; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D019294:Xanthomatosis, Cerebrotendinous / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D005938:Glucocorticoids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase
keywords: (tetrahydrocorticosterone+5α-tetrahydrocorticosterone)/11-dehydrocorticosterone ratio; 11β-hydroxysteroid dehydrogenase 1; 27-hydroxycholesterol; Cyp27a1 KO mice; cerebrotendinous xanthomatosis